Viagra and many other drugs were discovered by chance. Now science is hoping to change that.

Viagra, initially intended as a treatment for a heart condition, is just one of many drugs that have been repurposed for other uses. (PRN)

ByAimee Swartz

May 13

When a medication being developed to treat a heart condition gave patients erections, drugmakers knew they had a winner — not for angina, but for erectile dysfunction. That drug is now known as Viagra.

Figuring out that a drug developed for one ailment can be effective for another was once a matter of chance. In the case of Viagra, for example, the discovery emerged by observing an unintended but beneficial side effect. Now, technological and scientific advances are allowing researchers to rely more on science and less on luck in hopes of cutting the time and expense involved in getting new treatments to patients.

Scott Spangler, chief data scientist for life sciences at IBM Watson Health, said the approach is “especially promising” for patients with neglected diseases, including tuberculosis, malaria and certain tropical diseases, which impose significant social and financial burdens on developing countries. The repurposing process could also lead to new treatments for the thousands of diseases that are rare or have specific genetic mutations, which often lack treatment options. “The financial incentive for drugmakers to develop new drugs or vaccines for these diseases just isn’t there,” Spangler said.

The development of new drugs is a long, costly and risky process that most often ends in failure. Recent estimates suggest that the development of a new drug costs at least $1 billion over 10 years, with only a 10 percent chance of gaining approval from the Food and Drug Administration.

“Ask any parent who has been told their child has a fatal disease with no treatments, and they’ll tell you the traditional approach to drug development is not working,” said Bruce Bloom, CEO of Cures Within Reach, a nonprofit that funds repurposing research.

Developing a new treatment typically begins in the laboratory, where the drug is tested in biological specimens and animals to discover how it works and whether it is likely to be safe in humans. The drug is then given to people in clinical trials to assess its safety and efficacy.

By contrast, drug repurposing picks up somewhere in the middle of this process, building upon previous research. Drugs tested for repurposing include those that may have already been approved to treat a different disease, such as inexpensive generic drugs, along with drugs that have been put through millions of dollars’ and years’ worth of testing — some of which have proven safe in clinical trials — but were shelved before getting FDA approval.

“If you think of it as a race, you’re starting that much closer to the finish line,” Bloom said. “Because these drugs have already been extensively studied, including some testing in people, they are often able to skip pre­clinical testing requirements and, possibly, Phase I clinical trials, saving time and getting treatments to patients faster,” he said.

Compared with new drugs, Bloom said, repurposed ones are more than twice as likely to make it to patients, on a shorter time frame and at a fraction of the cost.

Viagra is just one of many repurposing successes. Others include raloxifene, an osteoporosis treatment that was later found to be effective in preventing breast cancer, and thalidomide, a discontinued morning-sickness medicine that caused severe birth defects but is now used to treat leprosy and multiple myeloma, a blood cancer.

Drugmakers develop new drugs to target a particular condition, but almost all drugs have “off-target activity,” with some drugs affecting several hundred genes and other biological processes, said Joel Dudley, director of the Institute for Next Generation Healthcare in New York. “The downstream effects of a drug for one disease could actually be the treatment for another,” he said.

Until recently, Dudley explained, finding new uses for existing drugs has been a mostly serendipitous process. “Today, instead of these discoveries occurring by chance, we can be purposeful in our approach,” he said.

Dudley said this is possible due to an “explosion” of available data — such as DNA sequences, imaging studies and health-care billing data — computer power, and sophisticated algorithms that mine data sets to predict how likely a drug is to treat another condition.

One example of computer power used in repurposing is IBM’s Watson, the machine-learning system that famously destroyed human competitors on the “Jeopardy” game show. It “can read, understand and draw parallels between millions of articles — in minutes,” Spangler said. After the supercomputer was trained on drugs that have shown promise in treating Parkinson’s disease, it was able to identify several other drugs that might be repurposed to treat the neurodegenerative disorder.

Atul Butte, director of the Institute for Computational Health Sciences at the University of California at San Francisco, also attributes a more systematic approach to repurposing to “an ever-increasing understanding” of the human genome, which has enabled researchers to reclassify diseases based on their genetic or molecular abnormalities rather than on their organ of origin. Genetic similarities that occur across diseases “can potentially be targeted by the same compound,” Butte said.

Butte’s lab developed an “opposites attract” computer algorithm to match drugs that move the activity of genes in one direction with a disease that moves genetic activity in the opposite direction. “It’s Match.com for drugs and diseases,” he said.

Last year, researchers in Butte’s lab used the computer algorithm to identify four drugs with potential for treating hepatocellular carcinoma, or HCC, the most common form of liver cancer and a leading cause of cancer-related death worldwide. Further testing showed that all four had anti-cancer effects, but one in particular, pyrvinium pamoate, which is approved for the treatment of pinworms, significantly reduced the growth of liver-cancer tumors in laboratory mice.

Whether the drug will prove effective in people with HCC remains to be seen. That would require a clinical trial, and funding is not always easy to come by.

Pharmaceutical companies rarely offer funding for repurposing generic drugs. Finding a second use for a drug, Bloom said, typically does not provide the same monetary returns as does creating new drugs, which are protected financially by patents. “No profit, no incentive,” he said.

As a result, financial backing often falls to philanthropic organizations, such as Bloom’s Cures Within Reach, which itself is funded exclusively by not-for-profit sources, or disease-based research organizations, such as the Leukemia and Lymphoma Society, the Michael J. Fox Foundation for Parkinson’s Research, Global Cures and the Britain-based Findacure.

“The good news is that repurposed drugs don’t necessarily require the time and expense of seeking FDA approval to help patients and be considered a success,” Bloom said. In fact, the majority of repurposing efforts funded by his organization do not seek FDA approval for a new indication but aim to provide enough evidence to treat patients “off-label,” which doctors can do at their discretion, particularly if no approved therapies exist or the patient has exhausted available treatment options.

That’s how children with autoimmune lymphoproliferative syndrome, or ALPS, an extremely rare and sometimes deadly autoimmune genetic disease, are now often thriving. Without treatment, children with ALPS suffer from swollen and painful lymph nodes and spleen, uncontrolled bleeding and increased infections.

After sirolimus, a drug used to prevent rejection in organ transplants, showed promise in slowing ALPS in mice, Children’s Hospital of Philadelphia conducted a pilot clinical trial to study the drug’s effect in children and adolescents with the disease; five of the six patients enrolled in the trial were in complete remission of the disease in a matter of months. Sirolimus is now used routinely to treat ALPS.

As for drugs that have failed initial trials, Dudley said that most drugmakers “want to let bad drugs lie,” even if there is evidence that drug could be repurposed to treat another disease. “I always make the joke that a failed drug is like Voldemort. If you try to talk about the drug, nobody wants to even hear its name anymore.”

Dudley says he’s optimistic that is changing through programs such as the Discovering New Therapeutic Uses for Existing Molecules program at the Center for Advancing Translational Sciences, or NCATS. Pharmaceutical companies partnering with the program have agreed to release abandoned drugs from their pipelines to researchers.

The program has supported 13 repurposing projects since it was established in 2012, including studies aimed at treating schizophrenia, thyroid cancer and Duchenne muscular dystrophy, a fatal muscle disease. Ten have led to clinical trials that continue to enroll patients.

Christine Colvis, director of drug development partnership programs at NCATS, said availability of these drugs will “encourage researchers to be creative in turning them into drugs for diseases that lack treatments.”

One of the program’s early successes involves testing saracatinib, originally developed by AstraZeneca as a cancer drug, as a treatment for people with Alzheimer’s. Just months after demonstrating that saracatinib reversed brain problems in mice with Alzheimer’s, researchers began testing it in humans — “a process that typically takes years,” said Colvis. Results of the trial are expected later this year.

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